scholarly journals Long Non-coding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization

Circulation ◽  
2021 ◽  
Author(s):  
Francesca Fasolo ◽  
Hong Jin ◽  
Greg Winski ◽  
Ekaterina Chernogubova ◽  
Jessica Pauli ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Vascular Tissue ◽  
Carotid Artery Disease ◽  
Atherosclerotic Lesion ◽  
Lesion Formation ◽  
Non Coding Rna ◽  
And Migration ◽  
Phenotypic Transition ◽  
Rna Transcript ◽  
Atherosclerotic Lesion Formation

Background: Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The current study assessed the functional contribution of the lncRNA Myocardial Infarction Associated Transcript ( MIAT ) to atherosclerosis and carotid artery disease. Methods: We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies (BiKE). The lncRNA MIAT was identified as the most upregulated non-coding RNA transcript in carotid plaques compared to non-atherosclerotic control arteries, which was confirmed by quantitative real time PCR (qRT-PCR) and in situ hybridization. Results: Experimental knockdown of MIAT , utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs), but also increased their apoptosis. Mechanistically, MIAT regulated SMC proliferation via the EGR1-ELK1-ERK pathway. MIAT is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of KLF4 and enhancing its transcription. Studies using Miat −/− and Miat −/− ApoE −/− mice as well as Yucatan LDLR −/− mini-pigs confirmed the regulatory role of this lncRNA in SMC de- and trans-differentiation and advanced atherosclerotic lesion formation. Conclusions: The lncRNA MIAT is a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs as well as the pro-inflammatory properties of macrophages.

scholarly journals A Critical Role of Platelet Adhesion in the Initiation of Atherosclerotic Lesion Formation

2002 ◽  
Vol 196 (7) ◽  
pp. 887-896 ◽  
Author(s):  
Steffen Massberg ◽  
Korbinian Brand ◽  
Sabine Grüner ◽  
Sharon Page ◽  
Elke Müller ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Platelet Adhesion ◽  
Critical Role ◽  
Atherosclerotic Lesion ◽  
Platelet Glycoprotein ◽  
Lesion Formation ◽  
Aortic Sinus ◽  
Major Player ◽  
Atherosclerotic Lesion Formation

The contribution of platelets to the process of atherosclerosis remains unclear. Here, we show in vivo that platelets adhere to the vascular endothelium of the carotid artery in ApoE−/− mice before the development of manifest atherosclerotic lesions. Platelet–endothelial cell interaction involved both platelet glycoprotein (GP)Ibα and GPIIb-IIIa. Platelet adhesion to the endothelium coincides with inflammatory gene expression and preceded atherosclerotic plaque invasion by leukocytes. Prolonged blockade of platelet adhesion in ApoE−/− mice profoundly reduced leukocyte accumulation in the arterial intima and attenuated atherosclerotic lesion formation in the carotid artery bifurcation, the aortic sinus, and the coronary arteries. These findings establish the platelet as a major player in initiation of the atherogenetic process.

Abstract 660: Inhibition of 14q32 “AngiomiR” MicroRNA-494 Reduces Atherosclerotic Lesion Formation, Increases Plaque Stability and Lowers Cholesterol Levels

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Sabine Welten ◽  
Anouk Wezel ◽  
Antonius Bastiaansen ◽  
Rob de Jong ◽  
Margreet de Vries ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Carotid Arteries ◽  
Target Genes ◽  
Expression Patterns ◽  
Atherosclerotic Lesion ◽  
Lesion Formation ◽  
Major Drawback ◽  
Plaque Stability ◽  
Cholesterol Levels ◽  
Atherosclerotic Lesion Formation

We have shown that inhibition of 14q32 microRNAs (miRs) miR-329, miR-487b, miR-494 and miR-495 increased both angiogenesis and arteriogenesis, leading to a 40% increase in blood flow recovery after ischemia. As many vascular remodelling processes share underlying mechanisms, we also investigated the effects of 14q32 microRNA inhibition in atherosclerosis When looking at expression patterns of 14q32 “angiomiRs”, we found that miR-494 was abundantly expressed in murine tissues involved in atherosclerosis, including the liver, spleen and carotid arteries. When looking at human carotid artery lesions, we found that miR-494 expression was doubled in vulnerable plaques compared to plaques of a stable phenotype. We used Gene Silencing Oligonucleotides (GSOs) to inhibit miR-494 in ApoE-/- mice, after placing semi-constrictive collars around both carotid arteries for 28 days to induce atherosclerotic lesion formation. We observed efficient uptake of IRD-800CW-labeled GSO-494 into the carotid artery, leading to a 50% reduction of miR-494 expression and significant upregulation of multiple anti-atherogenic target genes. Atherosclerotic lesion formation was drastically reduced in mice treated with GSO-494 (GSO-Control: 47 ± 11*103 μm2; GSO-494: 16 ± 3*103 μm2), while plaque stability was increased, determined by both a decrease in necrotic core size and an increase in plaque collagen content. Furthermore, inhibition of miR-494 resulted in increased cholesterol efflux in vitro (p<0,05). Indeed, in vivo, plasma total cholesterol levels and VLDL fractions were decreased after miR-494 inhibition (GSO-Control: 30.4 ± 1.1 mM; GSO-494: 26.4 ± 0.7 mM). In conclusion, inhibition of miR-494 results in smaller, more stable, atherosclerotic lesions, while simultaneously improving neovascularization. The so-called Janus phenomenon, which is a major drawback in translation towards the clinic, is hereby circumvented. The 14q32 miR-494 therefore provides a promising novel therapeutic target in prevention and treatment of atherosclerotic diseases.

Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL

10.1038/nm876 ◽  
2003 ◽  
Vol 9 (6) ◽  
pp. 736-743 ◽  
Author(s):  
Christoph J Binder ◽  
Sohvi Hörkkö ◽  
Asheesh Dewan ◽  
Mi-Kyung Chang ◽  
Emily P Kieu ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Molecular Mimicry ◽  
Oxidized Ldl ◽  
Pneumococcal Vaccination ◽  
Atherosclerotic Lesion ◽  
Lesion Formation ◽  
Atherosclerotic Lesion Formation

Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in LDL-Receptor Knockout Mice

2001 ◽  
Vol 88 (5) ◽  
pp. 506-512 ◽  
Author(s):  
Kazunobu Ishikawa ◽  
Daisuke Sugawara ◽  
Xu-ping Wang ◽  
Kazunori Suzuki ◽  
Hiroyuki Itabe ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Heme Oxygenase 1 ◽  
Lesion Formation ◽  
Ldl Receptor Knockout Mice ◽  
Atherosclerotic Lesion Formation

scholarly journals The onset of atherosclerotic lesion formation in hypercholesterolemic rabbits is delayed by iron depletion

FEBS Letters ◽  
1999 ◽  
Vol 459 (2) ◽  
pp. 218-222 ◽  
Author(s):  
Durairaj Ponraj ◽  
Jagoda Makjanic ◽  
Patricia S.P Thong ◽  
Benny K.H Tan ◽  
Frank Watt
Keyword(s):  
Atherosclerotic Lesion ◽  
Lesion Formation ◽  
Iron Depletion ◽  
Atherosclerotic Lesion Formation

Abstract 83: Bone Marrow Derived Cells Do Not Mediate Reductions in Cholesterol, Atherosclerosis and Adiposity in Microsomal Prostaglindin E Synthase 1 Deficient Mice Fed High Fat Diets Enriched in Cholesterol

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Sarah Srodulski ◽  
Victoria L King
Keyword(s):  
Bone Marrow ◽  
Weight Gain ◽  
Marrow Cell ◽  
Atherosclerotic Lesion ◽  
Chimeric Mice ◽  
High Fat ◽  
Lesion Formation ◽  
Bone Marrow Derived Cells ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Formation

Microsomal prostaglandin E 2 synthase-1 (mPGES-1) catalyzes the conversion of COX-2 generated PGH 2 to PGE 2 and is the predominate source of PGE 2 during and inflammatory response. We and others have demonstrated that mPGES-1 deficiency attenuates atherosclerosis in mice on a mixed background. The present study investigated the effect of mPGES-1 deficiency on atherosclerosis in C57BL/6 low density lipoprotein receptor deficient (LDLr-/-) mice. mPGES-1 deficiency attenuated atherosclerosis in LDLr-/- mice fed either a low fat (LF) (P = 0.02) or high fat (HF) (P = 0.0026) diet enriched with cholesterol, or a western diet (P = 0.02) for 17 weeks. mPGES-1 deficiency attenuated weight gain and cholesterol concentrations in mice fed a western (P = 0.004 and P < 0.05; respectively) or HF diet (P = 0.01 and P = 0.012, respectively). However, body weight and cholesterol concentrations were not different in mice fed the LF diet. These data suggest that different mechanisms mediate the reduction in atherosclerosis in mPGES-1 deficient mice fed LF and HF diets. To determine if mPGES-1 deficiency in macrophages contributed to the reduction in atherosclerosis in mice fed HF diets, 4 groups of chimeric mice were generated. Four weeks post bone marrow cell transplant (BMT) mice were fed a western diet. BMT attenuated weight gain in all groups of chimeric mice; however, weight gain was not different between any of the groups. BMT decreased atherosclerotic lesion formation 10 fold in all groups of mice. Neither bone marrow cell specific deficiency of mPGES-1 (KO>WT) or mPGES-1 specific expression in bone marrow derived cells (WT>KO) had an effect on lesion formation compared to WT>WT or KO>KO mice. Cholesterol concentrations were decreased in KO>KO and WT>KO mice compared to WT>WT (P < 0.01) and KO>WT (P< 0.05) mice. These data suggest that mPGES-1 expression in bone marrow derived cells does not contribute to the development of atherosclerosis. Moreover, these data suggest that prostanoids may play a role in hepatic cholesterol homeostasis in mice fed HF diets enriched in cholesterol thereby contributing to atherosclerotic lesion formation. Moreover, these data provide further evidence that prostanoids play a role in regulating the accumulation of diet-induced adiposity.

Abstract 3710: Estrogen Does not Account for Accelerated Atherosclerosis in LDLr−/− Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Victoria L King ◽  
Nicholas Hatch ◽  
Xuan Zhang ◽  
Lisa R Tannock
Keyword(s):  
Body Weight Gain ◽  
Atherosclerotic Lesion ◽  
Young Female ◽  
Lesion Formation ◽  
Accelerated Atherosclerosis ◽  
Female Mice ◽  
Ldl Particles ◽  
Gender Specific Differences ◽  
Event Rates ◽  
Atherosclerotic Lesion Formation

Clinical studies demonstrate less atherosclerosis in pre-menopausal women compared to age-matched men, but an equalization in atherosclerosis burden and cardiovascular event rates between genders following menopause. Conversely, using the LDLR−/− mouse model we and others have previously demonstrated that young female mice develop accelerated atherosclerosis compared to age matched males. Whether this difference is due to sex hormones or differences in metabolic factors is not clear. To determine if estrogen mediated the alterations in atherosclerosis in the female mice, female mice were ovariectomized (Ovx). Ovx mice had a marked reduction in uterus weight (Sham: 86 ± 1 vs Ovx: 26 ± 1mg, P < 0.001) and both Ovx females and males had greater body weight gain when fed a lard-enriched diet (10% kcal from fat, D12451 , Research Diets) for 17 weeks compared to sham females. Ovariectomy resulted in an increase in fasting glucose concentrations, which was comparable to males. Cholesterol and triglyceride concentrations were higher in both sham and Ovx females compared to males; primarily distributed in increased VLDL and LDL particles. Interestingly, ovariectomy had no significant effect on extent of atherosclerotic lesion formation in female mice and the extent of atherosclerotic lesion area in both female groups was significantly increased compared to male mice. These data suggest that gender specific differences in lipids and atherosclerotic lesion formation in female LDL-R deficient mice fed a diet enriched in lard are not mediated by estrogen.

Abstract 421: Aldose Reductase Protects Against the Early Atherosclerotic Lesion Formation InApoe-null Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Sanjay Srivastava ◽  
Oleg Barski ◽  
Aruni Bhatnagar
Keyword(s):  
Lipid Oxidation ◽  
Aldose Reductase ◽  
Atherosclerotic Lesion ◽  
Oxidation Products ◽  
Oxidized Lipids ◽  
Lesion Formation ◽  
Aortic Sinus ◽  
Unsaturated Lipids ◽  
Lipid Oxidation Products ◽  
Atherosclerotic Lesion Formation

Atherosclerotic lesion formation is associated with extensive oxidation of unsaturated lipids and the accumulation of lipid oxidation products. Products of lipid oxidation, particularly aldehydes, stimulate cytokine production and enhance monocyte adhesion. Aldehydes generated by oxidized lipids are metabolized by several biochemical pathways, of which aldose reductase (AR)-catalyzed reduction represents a metabolic fate common to both free and phospholipid esterified aldehydes. Herein, we tested the hypothesis that inhibition of AR could aggravate atherosclerotic lesion formation by preventing the removal and the detoxification of aldehydes generated by oxidized lipids. In atherosclerotic lesions of apoE-null mice, AR protein was associated with macrophage-rich regions and its abundance increased with lesion progression. Treatment of 8 week old apoE-null mice with AR inhibitors sorbinil or tolrestat for 4 weeks increased lesion formation in the aortic arch (P<0.01) and the aortic sinus (P<0.01). No change in lesion formation was observed when 24 week old mice were fed AR inhibitors for 12 weeks. To probe the role of AR in atherogenesis further, we generated AR −/− /apoE −/− mice. Lesions of 8 week old AR −/− /apoE −/− mice maintained on high fat diet for 4 or 12 weeks were significantly larger throughout the aortic tree (P<0.01 for both the groups) when compared with age-matched AR +/+ /apoE −/− mice. Lesions in AR −/− /apoE −/− mice exhibited increased collagen (P<0.01) and macrophage content (P<0.01) and a decrease in smooth muscle cells (P<0.01). GC-MS analysis showed that the concentration of AR substrates HNE and hexanal was increased by 2.5–3 fold (P<0.01) in the plasma of AR −/− /apoE −/− mice as compared with AR +/+ /apoE −/− mice. Immunohistochemical analysis showed greater accumulation of protein-HNE adducts in arterial lesions of AR −/− /apoE −/− mice. These observations suggest that AR is up regulated during atherosclerosis and that this protein protects against early stages of atherosclerotic lesion formation by removing aldehydes generated by lipid oxidation.

scholarly journals The Endogenous Estradiol Metabolite 2-Methoxyestradiol Reduces Atherosclerotic Lesion Formation in Female Apolipoprotein E-Deficient Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (9) ◽  
pp. 4128-4132 ◽  
Author(s):  
Johan Bourghardt ◽  
Göran Bergström ◽  
Alexandra Krettek ◽  
Sara Sjöberg ◽  
Jan Borén ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Low Dose ◽  
Hormone Replacement ◽  
Atherosclerotic Lesion ◽  
Total Serum ◽  
High Dose ◽  
Lesion Formation ◽  
Cholesterol Levels ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Formation

Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17β-estradiol (6 μg/d), or 2-methoxyestradiol [6.66 μg/d (low-dose) or 66.6 μg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P &lt; 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.

scholarly journals Increased Atherosclerotic Lesion Formation and Vascular Leukocyte Accumulation in Renal Impairment Are Mediated by Interleukin-17A

2013 ◽  
Vol 113 (8) ◽  
pp. 965-974 ◽  
Author(s):  
Shuwang Ge ◽  
Barbara Hertel ◽  
Ekaterina K. Koltsova ◽  
Inga Sörensen-Zender ◽  
Jan T. Kielstein ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Atherosclerotic Lesion ◽  
Lesion Formation ◽  
Leukocyte Accumulation ◽  
Interleukin 17A ◽  
Atherosclerotic Lesion Formation
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